It is well known that one gene mutation is not sufficient to trigger tumorigenesis, and therefore one urgent issue is to elucidate how various pro-oncogenic events work cooperatively in driving tumor initiation. Primary liver cancers, in particular hepatocellular carcinoma (HCC), are the 2nd leading cause of cancer-related deaths. Lack of understanding of the molecular pathogenesis for HCC has prevented us from designing mechanism-based therapeutic strategies. Mutations and silencing of Pten tumor suppressor have been detected in many liver cancer patients, but it is unclear how Pten deficiency interacts with other cell signaling disorders in promoting HCC development. Epidemiological analyses clearly indicate a strong association of HCC with chronic hepatitis B or C virus (HBV or HCV) infection in 80% of the diagnosed cases worldwide. However, the majority of hepatitis patients do NOT develop HCCs, indicating requirement of host cell defects in inducing hepato-oncogenesis. In most recent experiments, we found that additional deletion of Shp2 (a tyrosine phosphatase) in hepatocytes dramatically enhanced and accelerated HCC development induced by Pten loss. The Pten and Shp2 double knockout (DKO) mice developed HCCs at 100% penetrance in 7 months. Using this new compound mutant mouse line with defined kinetics of liver tumorigenesis and clear genetic defects, we will determine how Pten deficiency cooperates with additional tumor-promoting events in HCC development. We will also generate new mouse lines by crossing hepatocyte-specific Pten or Shp2 KO mouse with HBV transgenic mouse, to determine the dynamic interplay of viral infection with host cell defects in driving hepatopathogenesis. We will perform RNA-seq and bioinformatics analyses, to understand signaling pathways driving HCC initiation and also tumor cell-intrinsic as well as hepatic environmental signals required for tumorigenesis. We believe that in-depth molecular and cellular analyses of animal tumor models, using multidisciplinary tools, will be a most powerful approach to decipher the mechanisms underlying HCC initiation and progression.